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Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells.

ABSTRACT: Personalized in vitro models for dysplasia and carcinogenesis in the pancreas have been constrained by insufficient differentiation of human pluripotent stem cells (hPSCs) into the exocrine pancreatic lineage. Here, we differentiate hPSCs into pancreatic duct-like organoids (PDLOs) with morphological, transcriptional, proteomic, and functional characteristics of human pancreatic ducts, further maturing upon transplantation into mice. PDLOs are generated from hPSCs inducibly expressing oncogenic GNAS, KRAS, or KRAS with genetic covariance of lost CDKN2A and from induced hPSCs derived from a McCune-Albright patient. Each oncogene causes a specific growth, structural, and molecular phenotype in vitro. While transplanted PDLOs with oncogenic KRAS alone form heterogenous dysplastic lesions or cancer, KRAS with CDKN2A loss develop dedifferentiated pancreatic ductal adenocarcinomas. In contrast, transplanted PDLOs with mutant GNAS lead to intraductal papillary mucinous neoplasia-like structures. Conclusively, PDLOs enable in vitro and in vivo studies of pancreatic plasticity, dysplasia, and cancer formation from a genetically defined background.

SUBMITTER: Breunig M

PROVIDER: S-EPMC8461636 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells.

Breunig Markus M Merkle Jessica J Wagner Martin M Melzer Michael K MK Barth Thomas F E TFE Engleitner Thomas T Krumm Johannes J Wiedenmann Sandra S Cohrs Christian M CM Perkhofer Lukas L Jain Gaurav G Krüger Jana J Hermann Patrick C PC Schmid Maximilian M Madácsy Tamara T Varga Árpád Á Griger Joscha J Azoitei Ninel N Müller Martin M Wessely Oliver O Robey Pamela G PG Heller Sandra S Dantes Zahra Z Reichert Maximilian M Günes Cagatay C Bolenz Christian C Kuhn Florian F Maléth József J Speier Stephan S Liebau Stefan S Sipos Bence B Kuster Bernhard B Seufferlein Thomas T Rad Roland R Meier Matthias M Hohwieler Meike M Kleger Alexander A

Cell stem cell 20210428 6

Personalized in vitro models for dysplasia and carcinogenesis in the pancreas have been constrained by insufficient differentiation of human pluripotent stem cells (hPSCs) into the exocrine pancreatic lineage. Here, we differentiate hPSCs into pancreatic duct-like organoids (PDLOs) with morphological, transcriptional, proteomic, and functional characteristics of human pancreatic ducts, further maturing upon transplantation into mice. PDLOs are generated from hPSCs inducibly expressing oncogenic ...[more]

PMID: 33915078

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Project description:Infectious viruses so precisely fit their hosts that the study of natural viral infection depends on host-specific mechanisms that affect viral infection. For human parainfluenza virus 3, a prevalent cause of lower respiratory tract disease in infants, circulating human viruses are genetically different from viruses grown in standard laboratory conditions; the surface glycoproteins that mediate host cell entry on circulating viruses are suited to the environment of the human lung and differ from those of viruses grown in cultured cells. Polarized human airway epithelium cultures have been used to represent the large, proximal airways of mature adult airways. Here we modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids derived from human pluripotent stem cells contain mesoderm and pulmonary endoderm and develop into branching airway and alveolar structures. Whole-genome sequencing analysis of parainfluenza viruses replicating in the organoids showed maintenance of nucleotide identity, suggesting that no selective pressure is exerted on the virus in this tissue. Infection with parainfluenza virus led to viral shedding without morphological changes, while respiratory syncytial virus infection induced detachment and shedding of infected cells into the lung organoid lumens, reminiscent of parainfluenza and respiratory syncytial virus in human infant lungs. Measles virus infection, in contrast, induced syncytium formation. These human stem cell-derived lung organoids may serve as an authentic model for respiratory viral pathogenesis in the developing or infant lung, recapitulating respiratory viral infection in the host.IMPORTANCE Respiratory viruses are among the first pathogens encountered by young children, and the significant impact of these viral infections on the developing lung is poorly understood. Circulating viruses are suited to the environment of the human lung and are different from those of viruses grown in cultured cells. We modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids, derived from human pluripotent stem cells, develop into branching airway and alveolar structures and provide a tissue environment that maintains the authentic viral genome. The lung organoids can be genetically engineered prior to differentiation, thereby generating tissues bearing or lacking specific features that may be relevant to viral infection, a feature that may have utility for the study of host-pathogen interaction for a range of lung pathogens.

Dataset Information

Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells.

Publications

Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells.

Similar Datasets

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